Exploring Diseases/Traits and Blood Proteins Causally Related to Expression of ACE2, the Putative Receptor of SARS-CoV-2: A Mendelian Randomization Analysis Highlights Tentative Relevance of Diabetes-Related Traits.

Abstract

COVID-19 has become a major public health problem. There is good evidence that ACE2 is a receptor for SARS-CoV-2, and high expression of <i>ACE2</i> may increase susceptibility to infection. We aimed to explore risk factors affecting susceptibility to infection and prioritize drug repositioning candidates, based on Mendelian randomization (MR) studies on <i>ACE2</i> lung expression. We conducted a phenome-wide MR study to prioritize diseases/traits and blood proteins causally linked to <i>ACE2</i> lung expression in GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR, as these drugs may alter <i>ACE2</i> expression and may be clinically relevant. The most consistent finding was tentative evidence of an association between diabetes-related traits and increased <i>ACE2</i> expression. Based on one of the largest genome-wide association studies on type 2 diabetes mellitus (T2DM) to date (<i>N</i> = 898,130), T2DM was causally linked to raised <i>ACE2</i> expression (<i>P</i> = 2.91E-03; MR-IVW). Significant associations (at nominal level; <i>P</i> < 0.05) with <i>ACE2</i> expression were observed across multiple diabetes data sets and analytic methods for T1DM, T2DM, and related traits including early start of insulin. Other diseases/traits having nominal significant associations with increased expression included inflammatory bowel disease, (estrogen receptor-positive) breast cancer, lung cancer, asthma, smoking, and elevated alanine aminotransferase. We also identified drugs that may target the top-ranked proteins in MR, such as fostamatinib and zinc. Our analysis suggested that diabetes and related traits may increase <i>ACE2</i> expression, which may influence susceptibility to infection (or more severe infection). However, none of these findings withstood rigorous multiple testing corrections (at false discovery rate <0.05). Proteome-wide MR analyses might help uncover mechanisms underlying <i>ACE2</i> expression and guide drug repositioning. Further studies are required to verify our findings.